It has been well-demonstrated that the human immunodeficiency virus (HIV) causes immunodeficiency in its host via an ongoing, virally induced process. Several studies have shown that HIV-infected individuals have actively replicating virus throughout all stages of disease. In addition, the level of viral RNA in the peripheral blood is a predictor of time until disease onset. In general, a higher viral load equates to faster disease progression. These observations suggest that the virus is responsible for the depletion of CD4.sup.+ T cells and the destruction of the immune system. Less well understood is the mechanism by which HIV depletes its host of CD4.sup.+ T cells. One hypothesis is that the virus may kill the CD4.sup.+ T cell that it infects.
The lymphoid organs of infected individuals have been identified as the preferred location and continuous source of viral infection. In addition, the sensitive technique of polymerase chain reaction (PCR) has revealed high levels of virus in plasma and in peripheral blood cells throughout all stages of infection. These studies have provided evidence for a relationship between the levels of HIV RNA and disease progression, and argue strongly for a direct role of HIV replication in the pathogenesis of AIDS.
Studies of HIV cytopathicity using immortalized cell lines in culture, suggest that HIV infection directly kills CD4.sup.+ T cells and that, depending on the HIV strain studied, this killing is either by single-cell lysis or by syncytia formation. Furthermore, in vitro cytopathicity of primary viral isolates (that is, virus cultured directly from an infected individual) increases with disease progression. Thus, the ability of the virus to kill cells in vitro correlates with the progression to AIDS.
Of particular relevance is the fact that T lymphoblasts infected by HIV in vitro have been shown to die, or more precisely, undergo programmed cell death or apoptosis. Apoptosis is a regulated mechanism of cell suicide that is critical to many physiological processes, including T cell development and normal immune function. Apoptosis of peripheral blood mononuclear cells (PBMCs) from HIV-seropositive individuals has been previously described. Interestingly, previous studies show apoptosis of CD4.sup.+ T cells, and the majority of them also show apoptosis of CD8.sup.+ T cells.
Apoptosis has been described in animal models of AIDS, including macaques infected with a pathogenic strain of SIV, cats infected with feline immunodeficiency virus, and mice with murine AIDS (MAIDS). In addition, studies have documented the absence of apoptosis and anergy in SIV-infected African green monkeys and in HIV-infected chimpanzees, animals that support long-term productive infection, but that do not develop AIDS-like disease. The correlation between apoptosis and the development of AIDS suggests an etiological role for apoptosis in AIDS.
Although fourteen years have passed since identification of human immunodeficiency virus-1 (HIV-1) as the cause of AIDS, it is still not known how HIV kills its primary target, the T cell that carries the CD4 antigen. Thus, there remains a need to develop an effective reagent and therapy for the treatment of HIV infected CD4.sup.+ T cells.